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Cardiac Failure With Rosiglitazone
Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered [see BOXED WARNING].
Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled, echocardiographic trial was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤ 45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared with placebo during the 52-week trial. (See Table 1.)
Table 1: Emergent Cardiovascular Adverse Events in
Patients With Congestive Heart Failure (NYHA Class I and II) Treated With
Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF
N = 110
N = 114
|Cardiovascular deaths||5 (5%)||4 (4%)|
|CHF worsening||7 (6%)||4 (4%)|
|- with overnight hospitalization||5 (5%)||4 (4%)|
|- without overnight hospitalization||2 (2%)||0 (0%)|
|New or worsening edema||28 (25%)||10 (9%)|
|New or worsening dyspnea||29 (26%)||19 (17%)|
|Increases in CHF medication||36 (33%)||20 (18%)|
|Cardiovascular hospitalizationa||21 (19%)||15 (13%)|
|Ischemic adverse events||10 (9%)||5 (4%)|
|- Myocardial infarction||5 (5%)||2 (2%)|
|- Angina||6 (5%)||3 (3%)|
|a Includes hospitalization for any cardiovascular reason.|
In a long-term, cardiovascular outcome trial (RECORD) in patients with type 2 diabetes [see ADVERSE REACTIONS], the incidence of heart failure was higher in patients treated with rosiglitazone [2.7% (61/2,220) compared with active control 1.3% (29/2,227), HR 2.10 (95% CI: 1.35, 3.27)].
Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDARYL is not recommended in patients with symptomatic heart failure. [See BOXED WARNING.]
Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of AVANDARYL is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDARYL during this acute phase should be considered.
Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. AVANDARYL is not recommended in patients with NYHA Class III and IV cardiac status.
Congestive Heart Failure During Coadministration Of Rosiglitazone With Insulin
In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. Coadministration of rosiglitazone and insulin is not recommended. [See INDICATIONS AND USAGE, Major Adverse Cardiovascular Events]
In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis [see Major Adverse Cardiovascular Events], patients with type 2 diabetes mellitus were randomized to coadministration of rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, rosiglitazone was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 23 (2.3%) and 8 (1.0%) in the rosiglitazone plus insulin and insulin groups, respectively.
Heart Failure In Observational Studies Of Elderly Diabetic Patients Comparing Rosiglitazone To Pioglitazone
Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of hospitalized heart failure compared to use of pioglitazone. One other observational study in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients > 65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with rosiglitazone compared to pioglitazone in the older subgroup.
Major Adverse Cardiovascular Events
Data from long-term, prospective, randomized, controlled clinical trials of rosiglitazone versus metformin or sulfonylureas, particularly a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components. A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo.
Cardiovascular Events In Large, Long-term, Prospective, Randomized, Controlled Trials Of Rosiglitazone
RECORD, a prospectively designed cardiovascular outcome trial (mean follow-up 5.5 years; 4,447 patients), compared the addition of rosiglitazone to metformin or a sulfonylurea (N = 2,220) with a control group of metformin plus sulfonylurea (N = 2,227) in patients with type 2 diabetes [see ADVERSE REACTIONS]. Non-inferiority was demonstrated for the primary endpoint, cardiovascular hospitalization or cardiovascular death, for rosiglitazone compared with control [HR 0.99 (95% CI: 0.85, 1.16)] demonstrating no overall increased risk in cardiovascular morbidity or mortality. The hazard ratios for total mortality and MACE were consistent with the primary endpoint and the 95% CI similarly excluded a 20% increase in risk for rosiglitazone. The hazard ratios for the components of MACE were 0.72 (95% CI: 0.49, 1.06) for stroke, 1.14 (95% CI: 0.80, 1.63) for myocardial infarction, and 0.84 (95% CI: 0.59, 1.18) for cardiovascular death.
The results of RECORD are consistent with the findings of 2 earlier long-term, prospective, randomized, controlled clinical trials (each trial > 3 years' duration; total of 9,620 patients) (see Figure 1). In patients with impaired glucose tolerance (DREAM trial), although the incidence of cardiovascular events was higher among subjects who were randomized to rosiglitazone in combination with ramipril than among subjects randomized to ramipril alone, no statistically significant differences were observed for MACE and its components between rosiglitazone and placebo. In type 2 diabetes patients who were initiating oral agent monotherapy (ADOPT trial), no statistically significant differences were observed for MACE and its components between rosiglitazone and metformin or a sulfonylurea.
Figure 1: Hazard Ratios for the Risk of MACE,
Myocardial Infarction, and Total Mortality With Rosiglitazone Compared With a
Control Group in Long-term Trials
Cardiovascular Events In A Group Of 52 Clinical Trials
In a meta-analysis of 52 double-blind, randomized, controlled clinical trials designed to assess glucose-lowering efficacy in type 2 diabetes (mean duration 6 months), a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed [0.4% versus 0.3%; OR 1.8, (95% CI: 1.03, 3.25)]. A statistically non-significant increased risk of MACE was observed with rosiglitazone versus pooled comparators (OR 1.44, 95% CI: 0.95, 2.20). In the placebo-controlled trials, a statistically significant increased risk of myocardial infarction [0.4% versus 0.2%, OR 2.23 (95% CI: 1.14, 4.64)] and statistically non-significant increased risk of MACE [0.7% versus 0.5%, OR 1.53 (95% CI: 0.94, 2.54)] with rosiglitazone were observed. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE.
Mortality In Observational Studies Of Rosiglitazone Compared To Pioglitazone
Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of pioglitazone. One observational study in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to pioglitazone and reported similar results in the subpopulation of patients > 65 years of age. One additional small, prospective, observational study found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to pioglitazone.
AVANDARYL is a combination tablet containing rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. Debilitated or malnourished patients, and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. A starting dose of 1 mg glimepiride, as contained in AVANDARYL 4 mg/1 mg, followed by appropriate dose titration is recommended in these patients. [See CLINICAL PHARMACOLOGY] Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.
Patients receiving rosiglitazone in combination with a sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of the sulfonylurea may be necessary [see DOSAGE AND ADMINISTRATION].
AVANDARYL should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received 8 mg of rosiglitazone once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared with placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, AVANDARYL should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see BOXED WARNING, Cardiac Failure With Rosiglitazone, PATIENT INFORMATION].
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone, and may be dose-related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone [see ADVERSE REACTIONS]. The use of AVANDARYL in combination with insulin is not recommended [see Cardiac Failure With Rosiglitazone and Major Adverse Cardiovascular Events].
Dose-related weight gain was seen with AVANDARYL, rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 2). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
Table 2: Weight Changes (kg) From Baseline at Endpoint
During Clinical Trials [Median (25th, 75th Percentiles)]
|Duration||Contro Group||Rosiglitazone 4 mg||Rosiglitazone 8 mg|
|26 weeks||Placebo||-0.9 (-2.8, 0.9) N = 210||1.0 (-0.9, 3.6) N = 436||3.1 (1.1, 5.8) N = 439|
|52 weeks||Sulfonylurea||2.0 (0, 4.0) N = 173||2.0 (-0.6, 4.0) N = 150||2.6 (0, 5.3) N = 157|
|Duration||Contro Group||Rosiglitazone + Control Therapy|
|Rosiglitazone 4 mg||Rosiglitazone 8 mg|
|24-26 weeks||Sulfonylurea||0 (-1.0, 1.3) N = 1,155||2.2 (0.5, 4.0) N = 613||3.5 (1.4, 5.9) N = 841|
|26 weeks||Metformin||-1.4 (-3.2, 0.2) N = 175||0.8 (-1.0, 2.6) N = 100||2.1 (0, 4.3) N = 184|
|26 weeks||Insulin||0.9 (-0.5, 2.7) N = 162||4.1 (1.4, 6.3) N = 164||5.4 (3.4, 7.3) N = 150|
|AVANDARYL in Patients With Inadequate Control on Diet and Exercise|
|Duration||Contro||Group||AVANDARYL 4 mg/4 mg||AVANDARYL 8 mg/4 mg|
|28 weeks||Glimepiride||1.1 (-1.1, 3.2) N = 222||2.2 (0, 4.5) N = 221||2.9 (0, 5.8) N = 217|
|Rosiglitazone||0.9 (-1.4, 3.2) N = 228|
In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication, the median weight change (25th, 75th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.
In postmarketing experience with rosiglitazone alone or in combination with other hypoglycemic agents, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see BOXED WARNING].
With sulfonylureas, including glimepiride, there may be an elevation of liver enzyme levels in rare cases. In isolated instances, impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis (which may also lead to liver failure) have been reported.
Liver enzymes should be measured prior to the initiation of therapy with AVANDARYL in all patients and periodically thereafter per the clinical judgment of the healthcare professional.
Therapy with AVANDARYL should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤ 2.5X upper limit of normal) at baseline or during therapy with AVANDARYL should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDARYL in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to > 3X the upper limit of normal in patients on therapy with AVANDARYL, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain > 3X the upper limit of normal, therapy with AVANDARYL should be discontinued.
If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDARYL should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings. [See ADVERSE REACTIONS]
Long-term trials (ADOPT and RECORD) show an increased incidence of bone fracture in patients, particularly female patients, taking rosiglitazone [see ADVERSE REACTIONS]. This increased incidence was noted after the first year of treatment and persisted during the course of the trial. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of patients treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care.
There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, promptly discontinue AVANDARYL, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Decreases in hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone [see ADVERSE REACTIONS]. The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone.
Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride, a component of AVANDARYL, is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency [see ADVERSE REACTIONS].
Increased Risk Of Cardiovascular Mortality With Sulfonylureas
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Diabetes And Blood Glucose Control
When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDARYL and temporarily administer insulin. AVANDARYL may be reinstituted after the acute episode is resolved.
Periodic fasting glucose and HbA1c measurements should be performed to monitor therapeutic response.
Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking rosiglitazone [see Use in Specific Populations]. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials; therefore the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology], the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDARYL should be reviewed.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
There are multiple medications available to treat type 2 diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient.
Patients should be informed of the following:
- AVANDARYL is not recommended in patients with symptomatic heart failure.
- A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo. Data from long-term clinical trials of rosiglitazone versus other antidiabetes agents (metformin or sulfonylureas), including a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components.
- AVANDARYL is not recommended for patients who are taking insulin.
- Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy.
- It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin (HbA1c) tested. It can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of AVANDARYL.
- The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
- Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.
- Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDARYL should immediately report these symptoms to their physician.
- AVANDARYL should be taken with the first meal of the day.
- Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDARYL. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials so the frequency of this occurrence is not known.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride alone.
Rosiglitazone: Carcinogenesis: A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05 mg/kg/day, 0.3 mg/kg/day, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively).
Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ≥ 1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ≥ 0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.
Mutagenesis: Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.
Impairment Of Fertility: Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.
Glimepiride: Carcinogenesis: Studies in rats at doses of up to 5,000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation that was dose-related and was thought to be the result of chronic pancreatic stimulation. No adenoma formation in mice was observed at a dose of 320 ppm in complete feed, or 46 to 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.
Mutagenesis: Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse micronucleus test).
Impairment of Fertility: There was no effect of glimepiride on male mouse fertility in animals exposed up to 2,500 mg/kg body weight ( > 1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4,000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
Use In Specific Populations
Pregnancy Category C
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. AVANDARYL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There are no adequate and well-controlled trials with AVANDARYL or its individual components in pregnant women. Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown.
No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride individually.
Rosiglitazone: There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.
Glimepiride: In animal studies there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area). This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.
Labor And Delivery
The effect of AVANDARYL or its components on labor and delivery in humans is unknown.
No trials have been conducted with AVANDARYL. It is not known whether rosiglitazone or glimepiride is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue AVANDARYL, taking into account the importance of the drug to the mother.
Rosiglitazone: Drug-related material was detected in milk from lactating rats.
Glimepiride: During pre- and post-natal studies in rats, significant concentrations of glimepiride were present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride.
Safety and effectiveness of AVANDARYL in pediatric patients have not been established. AVANDARYL and its components, rosiglitazone and glimepiride, are not indicated for use in pediatric patients.
Rosiglitazone: Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see CLINICAL PHARMACOLOGY]. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older ( ≥ 65 years) and younger ( < 65 years) patients were observed.
Glimepiride: In clinical trials of glimepiride, 1,053 of 3,491 patients (30%) were ≥ 65 years. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤ 65 years (n = 49) and those > 65 years (n = 42) [see CLINICAL PHARMACOLOGY].
Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. Use caution when initiating AVANDARYL and increasing the dose of AVANDARYL in this patient population.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/19/2016
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